2-aminomethyl-4-exomethylenethiazoline epoxides

ABSTRACT

The present invention provides a novel process for preparing a 2-(aminomethyl)-4-thiazolemethanol. The compounds produced by the process of the present invention are useful for synthesizing anti-ulcer compounds such as Nizatidine.

This application is a continuation of application Ser. No. 07/952,426,filed on Sep. 28, 1992, now abandoned, which is a division ofapplication Ser. No. 07/703,526, filed on May 21, 1991, now abandoned.

BACKGROUND OF THE INVENTION

U.S. Pat. No. 4,904,792 teaches that Nizatidine,N-[2-[[[2-[(dimethylamino)methyl]-4-thiazolyl]methyl]thio]ethyl]-N'-methyl-2-nitro-1,1-ethenediamine,and related compounds of the general formula ##STR1## wherein

R¹ is hydrogen, methyl, ethyl, benzyl or benzoyl; R² is methyl or ethyl;or R¹ and R², taken together with the nitrogen atom to which they areattached, form a pyrrolidine, piperidene or morpholine ring;

R³ is hydrogen or methyl;

Z is --O-- or --S--;

n is 2 or 3;

Q is ##STR2## wherein

A is N--CN, N--NO₂, CH--NO₂, S, N--SO₂ --aryl, N--SO₂ --methyl orN--CO--NH₂ (where aryl is tolyl or phenyl); and

B is NHR, where R is methyl, ethyl, (2-hydroxy)ethyl or cyclopropyl, orYR⁴ where Y is --O-- or --S-- and R4 is C₁ -C₃ alkyl, --CH₂ --(C₂ -C₄alkenyl) or benzyl, are particularly effective H₂ -receptor antagonists,or are useful as intermediates in the preparation of suchpharmaceutically active compounds. As such, the patent compounds areuseful as anti-ulcer agents capable of inhibiting gastric acid secretionin mammals. Nizatidine, in particular, is an effective anti-ulcer drugcurrently sold under the trademark AXID.

U.S. Pat. No. 4,904,792 discloses Nizatidine, and the other relatedcompounds set forth in the patent, are synthesized using a multi-stepprocess. The first step of this process comprises reacting an acidaddition salt of an aminomethylthioacetamide with abeta-bromo-alpha-ketoester, such as ethyl bromopyruvate, so as toprovide an alkyl-2-(aminomethyl)-4-thiazolecarboxylate. Reduction ofsuch compound with a suitable hydride reducing agent yields a2-(aminomethyl)-4-thiazolemethanol compound, which is then converted toa [2-(aminomethyl)-4-thiazolylmethylthio]alkylamine by reaction withcysteamine or 3-mercaptopropylamine in the presence of an acid. Suchalkylamine is then readily converted to the pharmaceutically activecompounds of the patent via several different reaction pathways.

The process disclosed in U.S. Pat. No. 4,904,792 has severaldisadvantages which limit its utility on a production scale setting.Firstly, several of the reactants required by the patent's process arerather expensive. Secondly, the process yield, on a production scale, isless than desirable. Finally, the purity of the final product (which isdirectly related to the purity of the alkylamine intermediate), whenprepared on a production scale utilizing the procedure described above,is inconsistent and sometimes insufficient. When product of insufficientpurity is obtained, such product must be recrystallized in order toincrease purity to an acceptable level. Such recrystallization resultsin product loss thereby lowering process yield even further. All ofthese factors, when combined, render the process disclosed in U.S. Pat.No. 4,904,792 suitable for preparing laboratory scale quantities ofproduct, but less than desirable for preparing production scalequantities of same.

Accordingly, an object of the present invention is to provide a processfor preparing Nizatidine, and related compounds, which is eminentlysuitable for use in a production scale setting. The process of thepresent invention utilizes relatively inexpensive substrates to preparethe key alkylamine intermediate of U.S. Pat. No. 4,904,792. Furthermore,such key intermediate can be prepared in both high yield and purity. Assuch, the process of the present invention is believed to provide a moreeconomical synthesis for particularly useful anti-ulcer agents thanpreviously known routes for preparing such compounds.

SUMMARY OF THE INVENTION

The present invention provides a novel process for preparing a2-(aminomethyl)-4-thiazolemethanol having the formula ##STR3## whereinR¹ is hydrogen, methyl, ethyl, benzyl or benzoyl; R² is methyl or ethyl;or R¹ and R², taken together with the nitrogen atom to which they areattached, form a pyrrolidine, piperidine or morpholine ring; and R³ ishydrogen or methyl, which comprises reacting a4-hydroxy-4-chloromethyl-2-(aminomethyl)thiazoline of the formula##STR4## with an alkali metal base in an inert solvent. Thethiazolemethanol product produced by the process of the presentinvention is then readily converted to a[2-(aminomethyl)-4-thiazolylmethylthio]alkylamine, and ultimately tonizatidine or one of its related compounds as set forth in U.S. Pat. No.4,904,792, using the procedures described in that patent.

DETAILED DESCRIPTION OF THE INVENTION

The process of the present invention reacts a4-hydroxy-4-chloromethyl-2-(aminomethyl)thiazoline of the formula##STR5## with an alkali metal base in an inert solvent so as to providea 2-(aminomethyl)-4-thiazolemethanol of the formula ##STR6## Solventchoice for the process described above is not critical so long as thereactants are sufficiently solubilized to effect the desired reactionand the solvent is inert to the reaction conditions employed. Preferredinert solvents for use in the process of the present invention are thealcohol solvents, especially methanol, and the aromatic solvents,especially toluene. Toluene is the most preferred solvent for use in thepresent process.

Any number of conventional organic or inorganic alkali metal bases maybe employed in the process of the present invention. Typical organicbases which may be employed include the alkali metal alkoxides such assodium methoxide, potassium t-butoxide, sodium ethoxide, potassiummethoxide and the like. Typical inorganic bases which may be employedinclude the alkali metal hydroxides such as sodium hydroxide, potassiumhydroxide, lithium hydroxide and the like. The alkali metals themselves,such as sodium, potassium and the like, and the alkali metal hydridessuch as lithium hydride, sodium hydride and the like, may also beemployed as bases in the present process as well. The carbonateinorganic bases, such as sodium bicarbonate and potassium carbonate,however, do not appear to be suitable for use in the process of thepresent invention.

While the process of the present invention can employ any of the basesdiscussed above, potassium hydroxide provides a particularly preferredbase for meeting the object of the present invention. Potassiumhydroxide is inexpensive. Potassium hydroxide also allows synthesis ofthe 2-(aminomethyl)-4-thiazolemethanol product of the process of thepresent invention in higher yield and/or greater purity than any of theother organic or inorganic bases listed above. Since the2-(aminomethyl)-4-thiazolemethanol product is converted into the keyalkylamine intermediate of U.S. Pat. No. 4,904,792, the use of potassiumhydroxide in the present process plays a crucial role in providing aneconomical method of synthesizing Nizatidine and its related compoundsin high yield and purity. Accordingly, potassium hydroxide is aparticularly preferred base for use in the process of the presentinvention.

The amount of base required in the process of the present invention isalso not crucial. In general, at least an equimolar amount of base, or aslight excess thereof, relative to the4-hydroxy-4-chloromethyl-2-(aminomethyl)thiazoline substrate is employedin order to ensure that complete reaction of the thiazoline substrate isobtained. However, excess base, for example up to 5 equivalents of baserelative to the thiazoline substrate, may also be employed withoutdeleteriously affecting the desired reaction. A preferredbase/thiazoline substrate ratio ranges from about 1.3 equivalents ofbase to about 2.8 equivalents of base, with 1.3 equivalents of baserelative to the thiazoline substrate being the most preferredbase/thiazoline ratio.

As the base reacts with the thiazoline substrate of the presentinvention such substrate is converted to a2-(aminomethyl)-4-exomethylene-thiazoline epoxide of the formula##STR7## a salt (such as potassium chloride) and water. This epoxideintermediate then rearranges in-situ to provide the desired2-(aminomethyl)-4-thiazolemethanol product of the process of the presentinvention.

The salt produced by the reaction described above accumulates as thereaction proceeds. Depending on the type and amount of inert solventemployed, and the solubility of the salt in such solvent, saltprecipitation may occur before the process of the present invention iscomplete. To prevent salt precipitation, water may be added to thereaction mixture in a quantity sufficient to keep the salt in solution.Water addition may be accomplished by adding water directly, by addingwater in the form of an aqueous basic solution (for example an aqueouspotassium hydroxide solution) or a combination of both. Water additionis not required by the process of the present invention and is onlyutilized if prevention of salt precipitation is desired. Due to theexplosive nature of certain of the bases which may be employed in theprocess of the present invention, for example sodium metal, in somecases water addition should be avoided.

The concentration of thiazoline substrate and base in the inert solventis not critical. In general, it is desirable to use as concentrated asolution as possible in order to minimize any product loss which mightoccur during product isolation. However, sufficient solvent should beemployed in order to ensure that all reactants and reaction products(with the possible exception of the salt) stay in solution untilreaction is complete.

The process of the present invention is generally conducted at atemperature in the range of from about 0° C. to about 60° C. Whenconducted at a temperature in such range, the process of the presentinvention is generally substantially complete after about 15 minutes toabout 8 hours. Once the reaction is substantially complete, the2-(aminomethyl)-4-thiazolemethanol compounds prepared by the process ofthe present invention can be isolated using standard isolationtechniques such as extraction or distillation. Purification of theisolated compound may be accomplished using standard techniques such ashigh vacuum distillation, if desired.

The 2-(aminomethyl)-4-thiazolemethanol compounds prepared according tothe instant process are then readily converted to the key[2-(aminomethyl)-4-thiazolylmethylthio]alkylamine intermediate of U.S.Pat. No. 4,904,792 using procedures detailed in that patent. Thealkylamine intermediate can then, in turn, be converted to apharmaceutically active agent, such as Nizatidine, by utilizingprocedures set forth in U.S. Pat. No. 4,904,792.

As noted above, the process of the present invention employs a4-hydroxy-4-chloromethyl-2-(aminomethyl)thiazoline starting material.Such substrate is readily prepared from compounds which are eithercommercially available, or easily prepared from compounds which arecommercially available, according to the following reaction procedure##STR8## In the above procedure R¹, R² and R³ are as defined previouslyand X is a halogen atom.

In the above reaction, an acid addition salt of anaminoalkylthioacetamide is reacted with a slight excess (about 1.2equivalents) of a 1,3-dichloroketone so as to provide the4-hydroxy-4-chloromethyl-2-(aminomethyl)thiazoline starting material ofthe process of the present invention. The reaction is generallyconducted in an inert solvent such as methylene chloride or toluene.Furthermore, at least two equivalents of an acid scavenger, such assodium bicarbonate, should be employed in order to optimize reactionyield. The reaction should further be conducted at a temperature in therange of from 20° C. to 70° C., with 40° C. to 60° C. being an optimaltemperature range. When conducted at a temperature in the range of from20° C. to 60° C. the reaction will generally be substantially completeafter about 1 hour to about 24 hours. Once complete, the4-hydroxy-4-chloromethyl-2-(aminomethyl)thiazoline may be isolated, ifdesired, using standard isolation procedures. However, since thethiazoline compound is unstable and poses a severe health hazard,isolation of such compound is generally not preferred.

To obviate the instability and health problems posed by the thiazolinecompound such compound is preferably left in solution. This solution maybe readily employed in the process of the present invention once theacid salts produced by the process for preparing the thiazoline compoundhave been removed by standard isolation techniques.

The following examples illustrate specific aspects of the presentinvention. The examples are not intended to limit the scope of theinvention in any respect and should not be so construed.

EXAMPLE 1 4-Hydroxy-4-chloromethyl-2-(dimethylaminomethyl)thiazoline

A mixture of dimethylaminothioacetamide hydrochloride 54.0 g, 350 mmol),1,3-dichloroacetone (52.0 g, 409 mmol) and sodium bicarbonate (64.0 g,762 mmol) in 300 ml of toluene was stirred at 60° C. for 2 hours. Thehot reaction solution was then cooled and salts which had precipitatedduring the reaction were removed by filtration. An equal volume ofpetroleum ether was then added to the filtrate and solids precipitated.These solids were recovered by filtration to afford 55.5 g of titledcompound.

Twenty grams of the above material were further purified by dissolvingthem in 100 ml of a hot (60° C.) toluene solution. Any solids which didnot dissolve were removed by filtration, and the resulting filtrate wasslowly cooled to 10° C. while solids precipitated. These solids wererecovered by filtration, washed with petroleum ether and then driedunder nitrogen to afford 9.5 g of purified titled compound. Thispurified compound assayed by ¹ H and ¹³ C NMR, using tetramethylsilaneas internal standard, as follows:

¹ H NMR (toluene, 300.13 mHz) d=2.03 (s, 6H); 3.03 (d, 2H); 3.05 (d,2H); 3.10 (d, 2H); 3.22 (d, 2H) 3.52 (d, 2H); 3.67 (d, 2H).

¹³ C NMR (toluene, 75.47 mHz) d=39.09 (CH₂); 45.40 (CH₃); 50.13 (CH₂);61.14 (CH₂); 107.65 (C); 178.78 (C).

EXAMPLE 2 2-(Dimethylaminomethyl)-4-exomethylenethiazoline epoxide

To a solution of 0.14 g (0.67 mmol) of the compound of Example 2 in 5 mlof toluene were added 0.015 g (0.65 mmol) of sodium metal. The resultingmixture was stirred under nitrogen for one hour at 20° C. and thenfiltered. The filtrate was assayed by ¹ H and ¹³ C NMR, usingtetramethylsilane as internal standard, which assay indicated that thefiltrate contained titled compound. The assay results are as follows:

¹ H NMR (toluene, 300.13 mHz) d=1.94 (s, 6H); 2.28 (d, 2H); 2.72 (d,2H); 2.81 (d, 2H); 3.06 (s, 2H); 3.12 (d, 2H).

¹³ C NMR (toluene, 75.47 mHz) d=33.51 (CH₂); 45.40 (CH₃); 53.54 (CH₂);61.59 (CH₂); 87.06 (C); 179.24 (C).

EXAMPLE 3 2-(Dimethylaminomethyl)-4-thiazolemethanol

To a 3 liter, three-necked, flask equipped with an agitator andcondenser were added dimethylaminothioacetamide hydrochloride 270.0 g,1.75 mol), sodium bicarbonate (320.0 g, 3.81 mol), 1,3-dichloroacetone(260.0 g, 2.05 mol) and toluene (1.5 liters). The resulting solution washeated to 40° C. and stirred at that temperature for one hour. After onehour the reaction solution was heated to 60° C. and stirred at thattemperature for 3 hours. Solids which had precipitated during thereaction were then removed by filtration. Water (350 ml) was added tothe hot (40° C.) filtrate and the resulting two-phase solution wascooled to approximately 15° C. Potassium hydroxide [300 ml of a 45%(weight percent) aqueous solution] was added to the cool two-phasesolution at a rate such that the reaction mixture's temperature neverexceeded 20° C. Once potassium hydroxide addition was completed, thereaction was completed as well. The reaction mixture was then allowed towarm to room temperature and the organic and aqueous layers wereseparated. The aqueous layer was extracted with four 750 ml portions oftoluene. The toluene extracts and the above-mentioned organic layer werecombined. The resulting solution was reduced to a dark oil by vacuumdistillation (temperature 40° C.). This dark oil was then purified byhigh vacuum distillation (temperature 130°-140° C., pressure 1-2 mm Hg)to afford 232.4 g of a yellow oil which assayed according to the assayprocedure described below as titled compound. The purity of this oil wasgreater than 99.0%.

The product produced above was characterized by an HPLC comparison withan authentic reference standard. The assay sample was prepared byplacing 100 mg of product into a 50 ml volumetric flask, dissolving samewith 10 ml of acetonitrile and then diluting to volume with an ionpairing solution (the ion pairing solution was prepared by dissolving 2g of heptane sulfonic acid sodium salt in one liter of purified water,adding 1 ml of triethylamine and then adjusting the resulting solution'spH to 4.0 using glacial acetic acid). Ten milliliters of the dilutedsolution were transferred to a second 50 ml volumetric flask where theywere then further dilute with an additional 10 ml of acetonitrilefollowed by dilution to volume with ion pairing solution. Once the assaysample was prepared 10 μl of the sample were injected onto a 25 cmZorbax RX-C8 column. The detector had a wavelength of 254 nm, the columnflow rate was 1.5 ml/min and the column temperature was ambient.

EXAMPLE 4 2-(Dimethylaminomethyl)-4-thiazolemethanol

To a 100 ml, three-necked, flask equipped with an agitator and acondensor were added 3.0 g (0.014 mol) of4-hydroxy-4-chloromethyl-2-(dimethylaminomethyl)thiazoline (prepared asin Example 1), 45 ml of methanol and 4 ml of water. Potassium hydroxide[1.8 ml of a 45% (weight percent) aqueous solution] was added dropwiseto the reaction solution at a rate such that the reaction temperaturewas maintained at room temperature. Once potassium hydroxide additionwas completed, the reaction mixture was stirred at room temperature foran additional hour. A 1 ml sample of the reaction mixture was thenremoved from the flask, placed into a 50 ml volumetric flask and thendiluted to volume with a 4:1 (v:v) acetonitrile/water solution. Onemilliliter of the diluted sample solution was then placed in a 25 mlvolumetric flask and further diluted to volume with a 4:1 (v:v)acetonitrile/water solution. Ten microliters of this solution were thenassayed using the HPLC assay technique described in Example 3. Such HPLCassay indicated that 85.5% of the thiazoline substrate had converted tothe desired titled product.

EXAMPLE 5 2-(Dimethylaminomethyl)-4-thiazolemethanol

To a 100 ml, three-necked, flask equipped with an agitator and condensorwere added 3.0 g (0.014 mol) of4-hydroxy-4-chloromethyl-2-(dimethylaminomethyl)thiazoline (prepared asin Example 1), 47 ml of toluene, 1 ml of water and 0.79 g (0.014 mol) ofsolid potassium hydroxide. The resulting solution was stirred at roomtemperature for 45 minutes. A 1 μl sample of the reaction mixture wasthen removed from the flask and diluted according to the proceduredescribed in Example 4. The HPLC assay set forth in Example 3 indicatedthat 72.6% of the thiazoline substrate had converted to the desiredtitled product.

EXAMPLE 6 2-(Dimethylaminomethyl)-4-thiazolemethanol

The process of Example 5 was repeated using 0.56 g (0.014 mol) of solidsodium hydroxide in place of solid potassium hydroxide. The HPLC assayset forth in Example 3 indicated that 87.6% of the thiazoline substratehad converted to the desired titled product.

EXAMPLE 7 2-(Dimethylaminomethyl)-4-thiazolemethanol

The process of Example 5 was repeated using 3.0 g (0.014 mol) of4-hydroxy-4-chloromethyl-2-(dimethylaminomethyl)thiazoline (prepared asin Example 1), 48 ml of methanol and 0.98 g (0.014 mol) of potassiummethoxide. The HPLC assay set forth in Example 3 indicated that 70.1% ofthe thiazoline substrate had converted to the desired titled product.

EXAMPLE 8 2-(Dimethylaminomethyl)-4-thiazolemethanol

The process of Example 5 was repeated using 5.0 g (0.24 mol) of4-hydroxy-4-chloromethyl-2-(dimethylaminomethyl)thiazoline, 25 ml oft-butylalcohol and 2.69 g (0.024 mol) of potassium t-butoxide. The HPLCassay set forth in Example 3 indicated that 90% of the thiazolinesubstrate had converted to the desired titled product.

EXAMPLE 9 2-(Dimethylaminomethyl)-4-thiazolemethanol

To a 100 ml, three-necked, flask equipped with an agitator and acondensor were added 5.0 g (0.024 mol) of4-hydroxy-4-chloromethyl-2-(dimethylaminomethyl)thiazoline, 25 ml oftoluene and 1.3 g (0.024 mol) of sodium methoxide. The resultingsolution was stirred at room temperature for one hour and then volatileswere removed under reduced pressure to provide an oil. This oil was thenpurified by high vacuum distillation (temperature 123°-128° C., pressure1-2 mm Hg) to afford 1.74 g of a dark yellow oil which assayed by theHPLC assay described in Example 3 as titled compound.

EXAMPLE 10 2-(Dimethylaminomethyl)-4-thiazolemethanol

To a 100 ml, three-necked, flask equipped with an agitator and acondensor were added 3.0 g (0.014 mol) of4-hydroxy-4-chloromethyl-2-(dimethylaminomethyl)thiazoline and 45 ml ofmethanol. Sodium methoxide (0.78 g, 0.014 mol) was then dissolved in 15ml of methanol and the resulting solution was added dropwise to the 100ml flask at a rate such that the temperature of the flask's contents wasmaintained at room temperature. Once sodium methoxide addition wascomplete, the reaction mixture was stirred at room temperature for anadditional two hours. Salts which had formed in the reaction was thenremoved by filtration, after which volatiles were removed under reducedpressure to provide an oil. This oil was purified by adding it totoluene, filtering off any undissolved material and then removing thetoluene under reduced pressure to provide 1.99 g of an oil. This oilassayed by the HPLC assay described in Example 3 as titled compound.

EXAMPLE 11 2-(Dimethylaminomethyl)-4-thiazolemethanol

To a 100 ml, three necked, flask equipped with an agitator and acondensor were added 3.0 g (0.014 mol) of2-hydroxy-2-chloromethyl-2-(dimethylaminomethyl)thiazoline (prepared asin Example 1), 50 ml of toluene and 0.95 g (0.014 mol) of sodiumethoxide. The resulting solution was stirred at room temperature for 30minutes. A 1 ml sample of the reaction mixture was then removed from theflask and diluted according to the procedure described in Example 4. TheHPLC assay set forth in Example 3 indicated that 6.6% of the thiazolinesubstrate had converted to the desired titled compound.

EXAMPLE 12 2-(Dimethylaminomethyl)-4-thiazolemethanol

To a 100 ml, three-necked, flask equipped with an agitator and acondensor were added 3.0 g (0.014 mol) of2-hydroxy-2-chloromethyl-2-(dimethylaminomethyl)thiazoline (prepared asin Example 1), 50 ml of toluene and 0.34 g (0.014 mol) of sodiumhydride. The resulting solution was stirred at room temperature for 4hours. A 1 ml sample of the reaction mixture was then removed from theflask and diluted according to the procedure described in Example 4. TheHPLC assay set forth in Example 3 indicated that 66.8% of the thiazolinesubstrate had converted to the desired titled compound.

The following examples illustrate the conversion of the2-(aminomethyl)-4-thiazolemethanol compound produced by the process ofthe present invention into nizatidine.

EXAMPLE 13 [2-(Dimethylaminomethyl)-4-thiazolylmethylthio]ethylamine

Fifty grams (0.291 mol) of the compound of Example 3 were placed in a 1liter, three-necked, flask. To the flask was added a solution of 38.13 g(0.337 mol) of 2-aminoethanethiol hydrochloride dissolved in 73 ml of a37% (weight %) aqueous hydrochloric acid solution. Once such solutionwas added, the reaction mixture was heated to reflux and stirred at thattemperature for 15 hours. After 15 hours the reaction mixture was cooledto 95° C. and 142 ml of water were added. Cooling then continued untilthe solution temperature was approximately 15° C. Potassium hydroxide(132 ml of a 45% by weight aqueous potassium hydroxide solution) wasthen added in order to neutralize any unreacted acid. The resultingbasic solution was extracted several times with toluene. These extractswere combined and then reduced in volume to provide 160.4 g of a toluenesolution containing titled compound. This solution assayed as containing58.8 g of titled compound in the gas chromatography assay describedbelow. This same assay indicated that the toluene solution contained 6.7g of impurities.

The solution produced above was characterized by gas chromatographiccomparison with an authentic reference standard. The assay sample wasprepared by placing 500 mg of solution into a 50 ml volumetric flask andthen diluting to volume with methanol. The resulting solution was thentransferred to a 100 ml volumetric flask and then diluted to volume witha 6 mg/ml undecane/methanol solution. Once the assay sample was prepared2 82 l of the sample were injected onto a 6 foot×2 mm ID glass coilpacked with 5% Carbowax 20M on 100/120 mesh chromatography GAW DMCScolumn. The injector, detector and oven temperatures utilized were 250°C., 250° C. and 75° C., respectively.

EXAMPLE 14N-[2-[[[2-[(Dimethylamino)methyl]-4-thiazolyl]methyl]thio]ethyl-N'-methyl-2-nitro-1,1-ethenediamine

The toluene solution generated in Example 13 [99.6 g of solution; 50.0 g(0.216 mol) of the amine compound] was extracted three times with a 0.3%(weight %) sodium chloride solution. The aqueous extracts were combinedin a 1 liter flask and then concentrated under reduced pressure toprovide a solution weighing approximately 127 g. This solution wascooled to room temperature and 34.53 g (0.233 mol) ofN-methyl-1-methylthio-2-nitroethyleneamine were added. The resultingsolution was stirred at room temperature for 16 hours. After 16 hoursacetone (500 ml) and activated carbon (1.8 g) were added to the thick,tacky, reaction mixture. The resulting suspension was heated to reflux,held at that temperature for 30 minutes, and then filtered, while hot.The collected solids were washed with 20 ml of hot acetone. The filtrateand acetone wash were combined, seeded with authentic titled compoundand then allowed to cool to room temperature over a 1 hour period whilesolids precipitated. The resulting suspension was stirred at roomtemperature for 1 hour, cooled to 0° C. and stirred at that temperaturefor 30 minutes and then cooled to -10° C., The suspension was stirred at-10° C. for 4 hours and then filtered. The solids collected were washedwith cold acetone (375 ml), air dried for 30 minutes and then vacuumdried at 60° C. for 18 hours to provide 63.4 g of titled compound. m.p.130°-132° C. The HPLC assay described on pages 447 and 448 ofPharmacopeial Forum (May-June 1990) indicated that the titled compoundwas 99.4% pure on a solvent free basis.

The process of the present invention provides a method for synthesizingNizatidine, other related compounds and key intermediates thereto, whichis eminently suitable for use on a production scale. The substratesrequired by the present process are, in general, relatively inexpensive.The process steps required in order to synthesize Nizatidine and relatedcompounds can all, generally, be accomplished in high yield whilegenerating a minimum amount of impurities. Furthermore, what impuritiesare generated by the process for preparing Nizatidine and relatedcompounds detailed herein are easily removed at several stages in theprocess, thereby obviating the need to remove such impurities once thefinal, pharmaceutically active, product has been prepared. As such, thepresent process is believed to provide a highly efficient and economicalmethod for synthesizing pharmaceutically active anti-ulcer agents.

I claim:
 1. A compound of the formula ##STR9## wherein R¹ representshydrogen, methyl, ethyl, benzyl or benzoyl; R² represents methyl orethyl; or R¹ and R², taken together with the nitrogen atom to which theyare attached, form a pyrrolidine, piperidine or morpholine ring; andR³represents hydrogen or methyl.
 2. The compound of claim 1 wherein R¹ andR² are both methyl and R³ is hydrogen.